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Conformational dynamics between transmembrane domains and allosteric modulation of a metabotropic glutamate receptor
- Source :
- eLife, Vol 8 (2019), eLife
- Publication Year :
- 2019
- Publisher :
- eLife Sciences Publications Ltd, 2019.
-
Abstract
- Metabotropic glutamate receptors (mGluRs) are class C, synaptic G-protein-coupled receptors (GPCRs) that contain large extracellular ligand binding domains (LBDs) and form constitutive dimers. Despite the existence of a detailed picture of inter-LBD conformational dynamics and structural snapshots of both isolated domains and full-length receptors, it remains unclear how mGluR activation proceeds at the level of the transmembrane domains (TMDs) and how TMD-targeting allosteric drugs exert their effects. Here, we use time-resolved functional and conformational assays to dissect the mechanisms by which allosteric drugs activate and modulate mGluR2. Single-molecule subunit counting and inter-TMD fluorescence resonance energy transfer measurements in living cells reveal LBD-independent conformational rearrangements between TMD dimers during receptor modulation. Using these assays along with functional readouts, we uncover heterogeneity in the magnitude, direction, and the timing of the action of both positive and negative allosteric drugs. Together our experiments lead to a three-state model of TMD activation, which provides a framework for understanding how inter-subunit rearrangements drive class C GPCR activation.
- Subjects :
- Intravital Microscopy
Protein Conformation
glutamate receptor
QH301-705.5
Structural Biology and Molecular Biophysics
conformational dynamics
Science
Allosteric regulation
Class C GPCR
Receptors, Metabotropic Glutamate
General Biochemistry, Genetics and Molecular Biology
GPCRs
03 medical and health sciences
0302 clinical medicine
Allosteric Regulation
None
Fluorescence Resonance Energy Transfer
Biology (General)
030304 developmental biology
G protein-coupled receptor
0303 health sciences
General Immunology and Microbiology
Chemistry
General Neuroscience
General Medicine
3. Good health
Transmembrane domain
Förster resonance energy transfer
Structural biology
Metabotropic glutamate receptor
Biophysics
Medicine
Metabotropic glutamate receptor 2
030217 neurology & neurosurgery
Research Article
Neuroscience
Subjects
Details
- Language :
- English
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- eLife
- Accession number :
- edsair.doi.dedup.....0886f4df9c979ca8414490850b82f51e